XMU-MP-10 is a potent, specific, high-affinity inhibitor of HECT-type E3 ubiquitin ligase NEDD4 with MST KD of 43.92 nM, targets the HECT domain of NEDD4, significantly and selectively inhibits NEDD4 auto-ubiquitination.
XMU-MP-10 selectively inhibits NEDD4 auto-ubiquitination without affecting the ubiquitination activity of other E3 ligases from C2-WW-HECT subfamily, including NEDD4L, NEDL1, NEDL2, Smurf1, Smurf2, WWP1, WWP2, and ITCH.
XMU-MP-10 interacts with the HECT domain of NEDD4 at residues Y604, Y605, and Y634.
XMU-MP-10 induces the upregulation of β-TrCP, resulting in YAP degradation in a dose- and time-dependent manner in various TNBC cells, without affecting NEDD4 protein expression.
XMU-MP-10 (25 mg/kg, i.v. administration) significantly reduced the TNBC tumor growth in huPBMC-NCG mice engrafted with human TNBC cell MDA-MB-231, significantly increased intratumoral CD8+ T cell infiltration and reduced collagen deposition.
XMU-MP-10 influenced the β-TrCP-YAP-ECM axis in vivo, as decrease in YAP levels and upregulation of β-TrCP.